Hypoglycemia is the complication of diabetes most feared by insulin requiring diabetic subjects. The incidence of severe hypoglycemic reactions is increased as an unfortunate consequence of rigorous metabolic control. The Diabetes Control and Complications Trial (DCCT) has demonstrated that subjects with rigorous metabolic control experienced an -3 fold increase in severe hypoglycemic reactions and coma compared to the control group. Furthermore, this problem is not confined to IDDM patients as significant hypoglycemia also occurs in non-insulin- dependent diabetic (NIDDM) subjects treated with insulin or sulfonylurea drugs. In fact, the increase in severe hypoglycemia appears to be the major factor in determining whether rigorous metabolic control can confer any net benefit to diabetic subjects. While much has been learned in recent years about the hormonal and metabolic responses to hypoglycemia in normal individuals, and to some extent the defective response in IDDM subjects, many critical pieces of information are unknown. Of concern is the lack of available knowledge concerning the neuroendocrine response to hypoglycemia in NIDDM subjects. This is relevant as NIDDM subjects are likely to receive rigorous metabolic control as an extrapolation of the DCCT results. Recent data has demonstrated that the glycemic level is not, as was once thought, the only determinant of the neuroendocrine response to hypoglycemia. Age, gender, prevailing insulin level and antecedent hypoglycemia can all independently affect the neuroendocrine response to hypoglycemia. The deleterious effects of prior antecedent hypoglycemia appears to be implicated in the deficient autonomic- adrenomedullary responses to hypoglycemia observed in IDDM subjects. However, it is unknown, mechanically, how repeated hypoglycemia causes deficient subsequent neuroendocrine responses. The studies outlined in this proposal are aimed at furthering our understanding of the mechanisms involved in defective hypoglycemic counterregulation. The studies will be carried out in overnight fasted normal and diabetic man. The response to hypoglycemia will be assessed by measuring plasma hormones (insulin, glucagon, catecholamines, growth hormone, cortisol, ACTH, pancreatic polypeptide) and their metabolic consequences (glucose turnover, substrate levels) as well as neurophysiological parameters (peripheral sympathetic nerve activity with microneurography). Specifically the aims of this proposal are 1) to characterize the factors and mechanisms involved in the pathogenesis of the deficient autonomic-adrenomedullary response caused by prior repeated hypoglycemia in IDDM subjects; 2) to determine how the defective autonomic-adrenomedullary response to hypoglycemia may be improved in intensively treated IDDM subjects; and 3) to determine in NIDDM subjects the effects of acute and chronic elevations of insulin on the autonomic nervous system's response to hypoglycemia.